Endometrial cancer is the most common invasive gynecological cancer and the fourth most common cancer in women in the US. Projections indicate that there will be 40,100 new cases and an estimated 7000 deaths in 2005. Estrogen (through the estrogen receptor) provides the primary proliferative signal in the endometrium and controls critical cellular processes such as proliferation and differentiation in many tissues including uterus, breast, liver, brain. The estrogen receptor has historically been thought of as a ligand-dependent transcription factor that exerts its effects by gene regulation. Recent observations suggest that the estrogen and other steroid hormones elicit rapid activation of cellular signal transduction pathways these are termed extranuclear actions. The general objectives of these studies are to define the mechanisms by which estrogen rapidly activates cytoplasmic signaling pathways, and to examine the functional role of these pathways in endometrial cancer cell proliferation. This will be accomplished by determining growth profiles of endometrial cancer cells engineered to express only transcriptionally inactive estrogen receptor in response to estrogen. Biochemical assays and pharmacological inhibitors will be employed to determine the contribution of estrogen dependent signaling pathways to endometrial cancer cell proliferation. The mechanisms by which the estrogen receptor activates mitogen activated (MAP) kinases, PI3 kinase, protein kinase C and other signaling molecules will emphasize dissection of the protein-protein interactions that occur rapidly at the plasma membrane in response to estrogen. The role of PTEN in negatively regulating extranuclear estrogen receptor actions and consequent endometrial cancer cell proliferation will be investigated. Type 1 endometrial cancer is considered to be primarily a disease of unopposed estrogen. Obesity promotes a chronic estrogen environment and correlates with a 20 fold increase in the incidence of endometrial cancer; therefore, the increase in societal obesity will likely lead to and increase in endometrial cancer. The proposed studies will offer important insights into a subset of estrogen receptor actions that may provide potential targets for endocrine therapies. PUBLIC HEALTH RELEVANCE: Endometrial cancer is the most common invasive gynecological cancer and causes 7500 deaths per year. Endometrial cancer is caused by chronic estrogen stimulation. Rising obesity rates, early menarche, later child birth and extended years of menstuation all contribute to increased lifetime exposure to estrogen, and therefore are predicted to lead to dramatic increases in endometrial cancer incidence. Understanding novel mechanisms of estrogen receptor action may provide new targets for endocrine therapies.